Felodipine, the compound of Formula Ib, is a known vasodilator (Merck Index 11,3895 and references cited therein). Other phenyl-1,4-dihydro- pyridine compounds have also been disclosed which have therapeutic activity in the treatment of heart disease (see for example: U.S. Pat. Nos. 4,220,649; 4,705,797; 4,769,374; 4,806,544; 4,874,773; and EPO Appl. Nos. 0 089 167, 0 063 365 and 0 342 182). ##STR1##
The preparation of felodipine and related compounds typically involves a multistep synthesis, the last step of which usually involves formation of the dihydropyridine ring. Formation of the 4-aryl dihydropyridines has been accomplished by either simultaneous reaction of an aromatic aldehyde, an acetoacetate ester and a 3-aminocrotonic acid ester in an alcohol solvent (see for example U.S. Pat. No. 4,264,611) or a stepwise procedure of reacting an aromatic aldehyde with an acetoacetate ester and then reacting the resulting benzylidene with a 3-amino crotonic acid ester (see for example: EPO Appl. No. 0 319 814). Regardless of whether the sequence of reactions is a single step or two steps, the disclosed cycloadditions have always been thermally driven to completion. Thermal cycloaddition reactions have also been described which are carried out in the presence of an organic base or the acetic acid salt of an organic base (see for example U.S. Pat. No. 4,772,596 and EP-0 370 974). The two procedures are illustrated below. ##STR2##
EP - 0371492 discloses that when the latter reaction (R''=2-haloethyl) is carried out in the presence of a dehydrating agent such as molecular sieves, the desired aryldihydropyridine product is obtained in improved yields and with fewer by-products.
Other analogous processes for the preparation of felodipine are known in the art (see for example: Span. Appl. Nos. ES-536,229; 537,424; and 549,753).
In most of the disclosed syntheses of aryldihydropyridine diesters isolation of the product from the reaction mixture required an extractive workup that typically employed a halogenated solvent. Also because a low-molecular-weight alcohol is typically employed as a solvent in the cycloaddition reaction, such an extractive workup of the crude reaction requires that the solvent first be distilled away.
It is an object of the instant invention to provide a process, for the preparation of 4-substituted-1,4-dihydropyridines having shorter thermal reaction times, and, as a consequence, having lower weight percentages of undesirable impurities, than processes previously known in the art.
It has been surprisingly discovered that, under optimal reaction conditions designed to minimize the formation of impurities, the ring closure in the cycloaddition reaction of substituted 3-aminocrotonate and substituted benzylidine is not thermally driven to completion; rather, a strong acid can be added to the reaction mixture subsequent to the foreshortened heating period to catalyze and facilitate the complete cyclization to provide the 4-substituted-1,4-dihydropyridine.
It is also an object of the instant invention to provide an improved process for the preparation of felodipine having higher yields than processes previously known in the art.
It is further an object of the instant invention to provide a process for the preparation of felodipine wherein the crude felodipine is isolated by filtration of the reaction mixture, thereby eliminating the need for a more expensive and time-consuming extractive isolation procedure, which might employ environmentally harmful halogenated solvents.